The present invention relates to the field of vessel vasodilation and, more particularly, to methods for inducing or increasing the vasodilation of a vessel and methods for inducing or increasing the flow of fluid through a vessel by applying an electrical impulse to the vessel.
Despite procedural success rates greater than 95% achieved by percutaneous transluminal coronary angioplasty (PTCA), luminal renarrowing of blood vessels after balloon angioplasty occurs in 30% to 60% of all cases within 3 to 6 months. Smooth muscle cell proliferation and extracellular matrix remodeling appear to play pivotal roles in the luminal renarrowing process and negate the beneficial effect of vascular reconstruction by angioplasty (Leclercq et al., Arch. Mal. Coeur. Vaiss. 89:359-365 (1996)). The use of new technology, such as atherectomy, excimer laser, stent or rotablator (Hofling et al., Z. Kardiol. 80:25-34 (1991); Margolis et al., Clin. Cardiol. 14:489-493 (1991); Serruys et al., J. Am Coll. Cardiol. 17:143B1-154B (1991); Warth et al., J. Am. Coll. Cardiol. 34:641-648 (1994)) has not been able to reduce the incidence of restenosis significantly.
A variety of drugs also have been investigated to prevent luminal renarrowing in experimental animal and clinical settings, but without much success. A primary reason for this may be the failure of systemic administration to achieve effective concentrations of drugs at the targeted area. To overcome this deficiency, new endoluminal catheter delivery systems with various balloon configurations have been employed for localizing drug delivery. These include: hydrogel balloon, laser-perforated (Wolinsky balloon), xe2x80x98weeping,xe2x80x99 channel and xe2x80x98Dispatchxe2x80x99 balloons and variations thereof (Azrin et al., Circulation 90:433 (1994); Consigny et al., J. Vasc. Interv. Radiol 5:553 (1994); Wolinsky et al., JACC, 17:174B (1991); Riessen et al., JACC 23:1234 (1994); Schwartz, Restenosis Summit VII, Cleveland, Ohio, 1995, pp 290-294). Delivery capacity with hydrogel balloon is limited and, during placement, the catheter can lose substantial amount of the drug or agent that is administered. High pressure jet effect in Wolinsky balloon can cause vessel injury which can be avoided by making many holes,  less than 1 xcexcm, (weeping type). The xe2x80x98Dispatchxe2x80x99 catheter has generated a great deal of interest for drug delivery as it creates circular channels and can be used as a perfusion device, allowing continuous blood flow. However, each of these devices have limitations and have not been successful in resolving the problem of restenosis.
The cell membrane may be transiently permeabilized by subjecting cells to a brief, high intensity, electric field. This pulse-induced permeabilization of cell membranes, termed electroporation, has been used by investigators to introduce various compositions such as DNA, RNA, proteins, liposomes, latex beads, whole virus particles and other macromolecules into living cells (Hapala, Crit. Rev. Biotechnol. 17:105-122 (1997)). In particular, for example, large size nucleotide sequences (up to 630 Kb) can be introduced into mammalian cells via electroporation (Eanault et al., Gene 144:205 (1994); Nucl. Acids Res. 15:1311 (1987); Knutson et al., Anal. Biochem. 164:44 (1987); Gibson et al., EMBO J. 6:2457 (1987); Dower et al., Genetic Engineering 12:275 (1990); Mozo et al., Plant Molecular Biology 16:917 (1991)). These studies show that electroporation affords an efficient means to deliver therapeutic compositions such as drugs, genes, polypeptides and the like in vivo by applying an electrical pulse to particular cells or tissues within a subject. restenosis using angioplasty combined with electroporation to deliver drugs to a localized portion of coronary or peripheral arteries (Shapland et al., U.S. Pat. No. 5,498,238); treatment of cancer by electroporation in the presence of low doses of chemotherapeutic drugs (Mir, U.S. Pat. No. 5,468,223); introduction of functional genes for gene therapy (Nishi et al., Cancer Research 56:1050-1055 (1996)), electroporation of skin for the delivery of drugs into the skin or for the transdermal delivery of drugs across tissue (Zhang et al., Biochem. Biophys. Res. Comm. 220:633-636 (1996)); Weaver et al., U.S. Pat. No. 5,019,034; Prausnitz, Adv. Drug. Deliv. 18:395-425 (1996)). Hofmann describes a syringe apparatus for electroporating molecules and macromolecules into tissue regions in vivo in which the needles of the syringe used to deliver the molecules also function as electrodes (U.S. Pat. No. 5,273,525). Weaver describes an apparatus for the delivery of chemical agents into tissues in vivo via electroporation (U.S. Pat. No. 5,389,069). Hofmann et al., describe methods for delivering genes or drugs via electroporation to treat endothelial and other cells of blood vessels, for example, and an electroporation catheter device that can be used to practice the methods (U.S. Pat. No. 5,507,724). Crandell et al. describe the use of a catheter apparatus for introducing therapeutic macromolecules via electroporation into endothelial cells of a patients"" blood vessels (U.S. Pat. No. 5,304,120).
However, in view of the limited success in preventing luminal renarrowing after angioplasty, a need exists for the development of methods for inducing or increasing vessel vasodilation in order to treat undesirable vessel narrowing without therapeutic compositions, many of which elicit adverse side effects. The present invention satisfies this need and provides related advantages as well.
In accordance with the present invention, there are provided methods for inducing or increasing vasodilation of a vessel in a subject by applying an electrical impulse to the vessel, having sufficient strength and duration to induce or increase vasodilation of the vessel. Methods for inducing or increasing the flow of fluid through a vessel in a subject by applying an electrical impulse to the vessel, having sufficient strength and duration to induce or increase the flow of fluid through the vessel, also are provided. For example, a method of the invention employs an electrical impulse applied via electroporation. A method of the invention applies an electrical impulse with an electro-catheter apparatus. Invention methods are useful for treating clinical situations in which it is desired to increase or induce vessel vasodilation or to induce or increase the flow of fluid through the vessel.
Multiple electrical impulses can be applied in a method of the invention. An electrical impulse can be applied from about 50 to 90 volts per 1.5 mm. An electrical impulse can be applied for about 0.5 ms to 10 ms. Vessels can be denuded prior to, simultaneously with or after applying an electrical impulse in a method of the invention in order to augment the induction of vessel vasodilation or increase in the flow of fluid through the vessel.
Compositions can be administered to the vessel in the subject prior to, simultaneously with or after the application of an electrical impulse. Compositions can be administered locally or systemically. For example, a composition that inhibits cell proliferation, such as that associated with intimal thickening or hyperplasia or that inhibits platelet adhesion or aggregation, PDGF action, or matrix synthesis can be administered. Compositions useful in a method of the invention include but are not limted to are heparin, low molecular weight heparin and hirudin as well as angiotensin-converting enzyme inhibitor, colchicine, somatostatin analog and serotonin antagonist. Drugs, polynucleotides, polypeptides and chemotherapeutic agents also are included. A method of the invention can deliver a composition into the tunica intima, tunica media or tunica adventitia of the vessel, for example.
In another embodiment, the invention includes a method for inducing or increasing vasodilation of a vessel in a subject by applying an electrical impulse to the vessel using a catheter apparatus having at least one inflatable balloon portion, a first electrode, a second electrode positioned with respect to the first electrode and the subject where an electric field sufficient to induce or increase vasodilation of the vessel is generated by the electrical impulse. For example, a catheter apparatus having at least one infusion passage for administering a composition into a vessel of the subject is useful in a method of the invention. In one aspect, electrodes are positioned within the vessel.